Effects of Oleuropein on Hyperglycemia, Total Oxidant and Antioxidant Capacity in Streptozotosin-Diabetic Rats Treated with Metformin and Insulin

Abstract

In this study, it was aimed to investigate the effects of oleuropein on hyperglycemia and oxidant-antioxidant levels in metformin-insulin treated streptozotocin-diabetic rats. For this purpose, 40 Sprague-Dawley rats were used. Animals were divided into 5 groups as 4 experimental and 1 Control each containing 8 rats. 1 ml isotonic NaCl solution was injected intraperitoneally (ip) to the Control group while 50 mg/kg STZ ip was given to the G1, 50 mg/kg STZ + 100 mg/kg Metformin + 4 IU/kg insulin ip was given to the G2, 50 mg/kg STZ + 100 mg/kg Metformin + 4 IU/kg insulin ip and 30 mg/kg orally oleuropein was given to the G3 and 50 mg/kg STZ ip and 30 mg/kg oleuropein orally was given to the G4. Blood glucose values were statistically higher in the experimental groups than the control after streptozotocin administration (P<0.001, P<0.01, P<0.01 respectively). Plasma Total Antioxidant Capacity (TAC) of G2 and G3 were statistically higher than G1 (P<0.001). It was found that plasma TAC levels of G3 were statistically higher than the control (P<0.05). It was determined that the G1 (P<0.001), G2 (P<0.01) and G3 (P<0.05) group had significantly higher plasma Total Oxidant Capacity (TOC) than the control group. TAC levels in the liver of the experimental groups were determined to be statistically insignificant according to the control group. The liver TOC levels of the G2 and G4 group were significantly higher than the control group (P<0.01, P<0.001 respectively). In conclusion, the use of oleuropein alone did not affect the blood glucose level, the live weight, the plasma and the liver TAC and TOC levels, but the use of metformin and insulin with oleuropein as an antioxidant and free radical scavenger following to the rising oxidation in diabetes were supported and strengthen the system.

Keywords

• Diabet
• Insulin
• Metformine
• Oleuropein
• TAC
• TOC

Streptozotosin ile Diyabet Oluşturulmuş ve Metformin-İnsülin ile Diyabet Tedavisi Gören Ratlarda, Oleuropeinin Hiperglisemi, Total Oksidan ve Total Antioksidan Düzeyleri Üzerine Etkileri

Abstract

Bu çalışmada, streptozotosin ile diyabet oluşturulmuş ve metformin ve insülin ile diyabet tedavisi gören ratlarda, oleuropeinin hiperglisemi, oksidan-antioksidan düzeyleri üzerine etkilerinin araştırılması amaçlandı. Bu maksatla, 40 adet erkek Sprague Dawley rat kullanıldı. Ratlar her grupta 8 hayvan bulunacak şekilde 4 deney ve 1 kontrol grubu olmak üzere 5 gruba ayrıldı. Kontrol grubuna %0.09 NaCl intraperitoneal (ip) uygulandı. G1’e 50 mg/kg STZ ip, G2’ye 50 mg/kg STZ + 100 mg/kg metformin + 4 İU/kg insülin ip, G3’e 50 mg/kg STZ + 100 mg/kg metformin + 4 İU/kg insülin ip ve 30 mg/kg oleuropein oral olarak ve G4’e 50 mg/kg STZ ip olarak ve 30 mg/kg oleuropein oral olarak uygulandı. Streptozotosin uygulandıktan sonraki 3, 10 ve 21. günlerde deneme gruplarının kan glukoz değerleri kontrol grubuna göre istatistiksel olarak önemli düzeyde yüksek bulunmuştur (sırasıyla P<0.001, P<0.01, P<0.01). Plazma total antioksidan kapasiteleri gruplar arasında kıyaslandığında, G2 ve G3 grubunun Total Antioksidan Kapasite (TAC) düzeyleri, G1 grubuna göre istatistiksel olarak daha yüksek belirlenmiştir (P<0.001). Kontrol grubu ile deneme gurupları arasında kıyaslama yapıldığında G3 grubunun TAC düzeylerinin, kontrol grubuna göre istatistiksel olarak yüksek olduğu belirlenmiştir (P<0.05). G1 (P<0.001), G2 (P<0.01) ve G3 (P<0.05) grubunun plazma Total Oksidan Kapasitelerinin (TOC) kontrol grubuna göre istatistiksel olarak yüksek olduğu belirlenmiştir. Deneme gruplarının karaciğer TAC düzeylerinin kontrol grubuna göre istatistiksel olarak önemsiz olduğu tespit edildi. Karaciğer total oksidan kapasiteleri gruplar arasında kıyaslandığında G2 grubu ile G4 gurubunun TOC düzeylerinin kontrol grubuna göre istatistiksel olarak yüksek olduğu (sırasıyla P<0.01, P<0.001) belirlenmiştir. Sonuç olarak oleuropeinin tek başına kullanımının kan glukoz düzeyini, canlı ağırlığı ve plazma ile karaciğer TAC ve TOC kapasitelerini etkilemediği, ancak diyabette yükselen oksidasyona karşılık, metformin ve insülinle birlikte kullanımının antioksidan sisteme destek olduğu ve serbest radikal tutucu etkiyi kuvvetlendirdiği düşünülmektedir.

Keywords

• Diabet
• İnsulin
• Metformine
• Oleuropein
• TAC
• TOC

References

1. Abou-Seif MA, Youssef AA, 2004: Evaluation of some biochemical changes in diabetic patients. Clinica Chimica Acta, 346, 161–170.
2. Al-Azzawie HF, Alhamdani MS, 2006: Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits. Life Sci, 78, 1371-1377.
3. American Diabetes Association (ADA) 2005: Standards of medical care in diabetes, Diabetes Care 28, 34-36.
4. Asgary S, Naderi GA, Sarraf ZN, Vakili R, 2002: The inhibitory effects of pure flavonoids on in vitro protein glycosylation. J Herb Pharmacother, 2, 47–55.
5. Aslan M, Orhan DD, Orhan N, Sezik E, Yeşilada E, 2007: In vivo antidiabetic and antioxidant potential of Helichrysum plicantaum ssp. Plicatum capitulums in streptozotocin-induced-diabetic rats. J Ethonopharmacol, 109, 54–59.
6. Cusi K, DeFronzo RA, 1998: Metformin: a review of its metabolic effects. Diabetes Rev, 6, 89-131.
7. Davie SJ, Gould BJ, Yudkin JS, 1992: Effect of vitamin C on glycosylation of proteins. Diabetes, 41, 167–173.
8. Emanuelli B, Glondu M, Filloux C, Peraldi P, Obberghen EV, 2004: The potential role of SOCS-3 in the interleukin-induced desensitization of insulin signaling in pancreatic-cells. Diabetes, 53, 97-103.

9. Farah R, Shurtz-Swirski R, Lapin O, 2008: Intensification of oxidative stress and inflammation in Type 2 diabetes despite antihyperglycemic treatment. Cardiovasc Diabetol, 7, 20.
10. Galli C, Visioli F, 1999: Antioxidant and other activities of phenolics in olives/olive oil, typical components of the mediterranean diet. Lipids, 34, 23-26.
11. Garrido-Fernandez A, Fernandez-Diez MJ, Adams MR, 1997: Table Olives: Production and Processing. 1st ed., 495, Chapman & Hall, London, UK.
12. Kumar RS, Anthrayose CV, Iyer KV, Vimala B, Shashidhar S, 2001: Lipid peroxidation and diabetic retinopathy. Indian Med Sci, 55, 133-138.
13. Lean ME, Noroozi M, Kelly I, Burns J, Talwar D, Sattar N, Crozier A, 1999: Dietary flavonols protect diabetic human lymphocytes against oxidative damage to DNA. Diabetes, 48, 176–181.
14. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC, 2011: Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer, 11, 20.
15. Lee SH, Kwon KI, 2004: Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers. Arch Pharm Res, 27, 806-810.
16. Lhommeau I, Douillard S, Bigot E, Benoit I, Krempf M, Patrice T, 2011: Serum resistance to singlet oxygen in patients with diabetes mellitus in comparison to healthy donors. Metabolism, 60, 1340-1348,
17. Li X, Zhang N, Li Y, Shi Y, Li D, Xie Y, Ming J, 2011: Effects of metformin and rosiglitazone on peripheral insulin resistance and β-cell function in obesity: a double-blind, randomized, controlled study. J Int Med Res, 39, 358-365.
18. Montes-Cortes DH, Hicks JJ, Ceballos-Reyes GM, Garcia-Sanchez JR, Medina-Navarro R, Olivares-Corichi IM, 2010: Chemical and functional changes of human insulin by in vitro incubation with blood from diabetic patients in oxidative stres. Metabolism, 59, 935-942.
19. Niwa A, Tajiri T, Higashino H, 2011: Ipomoea batatas and agarics blazei ameliorate diabetic disorders with therapeutic antioxidant potential in streptozotocininduced diabetic rats. J Clin Biochem Nutr, 48, 194-202.
20. Novelli M, Fabregat ME, Fernandez-Alvarez J, Gomis R, Masiello P, 2001: Metabolic and functional studies on isolated islets in a new rat model of Type 2 diabetes. Molecular and Cell Endocrin, 175, 57-66.
21. Novelli M, Pocai A, Lajoix AD, Beffy P, Bezi D, Marchetti P, Gross R, Masiello P, 2004: Alteration of β-cell constitutive NO synthase activity is involved in the abnormal insulin response to arginine in a new rat model of Type 2 diabetes. Mol Cell Endocrin, 219, 77-82.
22. Özata M, Yönem A, 2006: Endokrinoloji Metabolizma ve Diyabet. 1st ed., 275-343, İstanbul Medikal Yayıncılık, İstanbul, Türkiye.
23. Pan HZ, Zhang H, Chang D, Li H, Sui H, 2008: The change of oxidative stress products in diabetes mellitus and diabetic retinopathy. Br J Ophthalmol, 92, 548–551.
24. Pirie FJ, Omar M, Motala AA, Amod A, 1996: The Genetics of non insulin dependent diabetes mellitus (NIDDM) in Africa. Int J Dia Dev Count, 16, 36-40.
25. Schneider J, 1991: Effects of metformin on dyslipoproteinemia in non-insulindependent diabetes mellitus. Diabet Metab, 17, 185-190.
26. Sheetz MJ, King GL, 2002: Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA, 288, 2579–2588.
27. Sinclair AJ, Girling AJ, Gray L, Lunec J, Barnett AH, 1992: An investigatio of the relationship between free radical activity and vitamin C metabolism in elderly diabetic subjects with retinopathy. Gerontology, 38, 268–274.
28. Singh I, Mok M, Christensen AM, Turner AH, Hawley JA, 2008: The effects of polyphenols in olive leaves on platelet function. Nutr Metab Cardiovasc Diseas, 18, 127-132.
29. Sliwinska A, Blasiak J, Drzewoski J, 2006: Effect of gliclazide on DNA damage in human peripheral blood lymphocytes and insulinoma mouse cells. Chem-Bioll Interact, 162, 259-267.
30. Stepensky D, Friedman M, Raz I, Hoffman A, 2002: Pharmacokinetic pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab Dispos, 30, 861-868.
31. Tetik HD, 2005: Sofralık Zeytin İşleme Teknikleri. 5th ed., 136, Emre Basımevi, İzmir, Türkiye.
32. Tripoli E, Giammanco M, Tabacchi G, Majo DD, Giammanco S, Guardia LM, 2005: The phenolic compounds of olive oil: structure, biological activity and beneficial effects on human health. NutrRes Rev, 18, 112.
33. Tsimidou M, 1998: Polyphenols and quality of virgin olive oil in retrospect. Ital J Food Sci, 10, 99-116.
34. Üstüner MC, 1999: The Effects of Acarbose and Rumex Patientia L. (Labada) in Experimental Animals with Type II Diabetes. Yüksek Lisans Tezi, OGÜ Sağlık Bilimleri Enstitüsü, Eskişehir.
35. Visioli F, Galli C, 1994: Oleuropein protects LDL from oxidation. Life Sci, 55, 1965-971.
36. Visioli F, Galli C, 1995: Natural antioxidants and prevention of coronary heart disease: the potential role of olive oil and its minor constituents. Nutr Metab Cardovasc Dis, 5, 306-331.
37. Vlahov G, 1992: Flavonoids in three olive (Olea europaea) fruit varieties during maturation. J Sci Food Agric, 58, 157-159.
38. Wolff SP, 1993: Diabetes mellitus and free radicals: Free radicals, transition metals and oxidative stress in the etiology of diabetes mellitus and complications. British Medical Bulletin, 49, 642-52.
39. Xie Z, Zhang J, Wu J, Viollet B, Ming-Hui Z, 2008: Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes, 57, 3222–3230.
40. Yenigün M, 2001: Her Yönü ile diabetes mellitus. 1st ed., 8-80, Nobel Tıp, İstanbul, Türkiye.